All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Pituitary tumors, accounting for ˜15% of intracranial tumors, are invariably benign monoclonal adenomas and cause significant morbidity due to abnormal hormone secretion, and/or tumor mass effects compressing vital structures1. Adrenocorticotropic hormone(ACTH)-secreting tumors arising from pituitary corticotroph cells (Cushing's disease) exhibit poor prognosis, and cause hypercortisolemia resulting in osteoporosis, infections, psychiatric disorders, muscle atrophy, fat accumulation, hypertension, hyperglycemia and ultimately death2-4.
Cushing's syndrome is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol. Sometimes called hypercortisolism, Cushing's syndrome is relatively rare and most commonly affects adults aged 20 to 50. People who are obese and have type 2 diabetes, along with poorly controlled blood glucose and high blood pressure, have an increased risk of developing the disorder. The abnormal exposure of the body to cortisol can result from a variety of physiological conditions and diseases. Treatment depends on the specific reason for excess cortisol and may include surgery, radiation, chemotherapy, or the use of cortisol-inhibiting drugs. If the cause is long-term use of glucocorticoid hormones to treat another disorder, the physician may gradually reduce the dosage to the lowest dose adequate for control of that disorder. Once control is established, the daily dose of glucocorticoid hormones may be doubled and given on alternate days to lessen side effects. In some cases, noncorticosteroid drugs can be prescribed.
No drug effectively targets ACTH-secreting pituitary adenomas. Current optimal treatment is surgical resection, with initial remission rates achieved by an expert pituitary surgeon ranging from 65-90% for microadenomas, and less than 65% for macroadenomas2. Post-operative recurrence rates for microadenomas are 10-20% at 10 years, and up to 45% for macroadenomas2. Surgery is further challenged by the fact that pre-operative pituitary tumor localization is often difficult even using high-resolution MRI, and inferior petrosal sinus sampling is often required for ACTH measurements to confirm the presence of a tumor5-7. Early results with the somatostatin analog pasireotide, or the dopamine agonist cabergoline have shown short-term biochemical remission in a minority of patients with Cushing's disease8,9. Long-term side effects and efficacy of these medications in patients with Cushing's disease are unknown, and pasireotide may predispose to hyperglycemia10.
Epidermal growth factor (EGF) receptor activation, either as a result of a mutation, or due to ligand or receptor overexpression, is associated with a variety of human cancers11. EGF is also a mitogen for pituitary cells, and induces prolactin and ACTH synthesis12. Although pituitary tumors, including ACTH-secreting adenomas, express the EGF receptor13-16, the role of the receptor in tumorigenesis remains unclear. In pituitary corticotroph tumors expressing the EGF receptor, p27Kip1, a cyclin-dependent kinase inhibitor, was down-regulated16. Mice with disrupted p27 also develop pituitary tumors mostly expressing proopiomelanocortin (POMC), a precursor protein of ACTH17-20. Applicants therefore tested the function of EGF receptor (EGFR) signaling in ACTH-secreting pituitary adenomas, and hypothesized that the receptor could be a novel target for therapy of Cushing's disease.
Gefitinib (marketed as Iressa® by AstraZeneca and Teva), a tyrosine kinase inhibitor (TKI) targeting the EGFR, blocks activity at the ATP-binding site of the intracellular tyrosine kinase domain21. Gefitnib is a selective inhibitor of the epidermal growth factor receptor's (EGFR's) tyrosine kinase domain, and thus acts as an EGFR inhibitor. It is approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy. Gefitinib exhibits efficacy in treating pulmonary adenocarcinoma, especially in female Asian nonsmokers. In these populations, a somatic mutation, either a deletion mutant of exon19 (del746_A750) or point mutation of exon21 (L858R) has been observed22. In other cancers which overexpress EGFR (either wild type or mutants), gefitinib has also been shown to be effective23,24. Here, Applicants show the functional role of EGFR in murine and canine corticotroph tumors and provide evidence supporting the use of gefitinib as a novel targeted therapy for Cushing's disease in subjects.
There is currently a need in the art for additional treatments for Cushing's Disease or hypercortisolism.